Despite improvements in worldwide health and advances in medical practice the incidence of preterm birth continues to rise in virtually every region of the globe and is accounts for nearly 15% of all live births in the United States. Associated with this increased population of very low birth-weight infants are several medical conditions that are both life threatening and costly. One of these conditions is necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. An important feature of this application is the investigation of nicotinamide (known inhibitor of PARP) as a potential therapeutic agent for NEC. We will carry out preclinical studies to define mechanistic actions and identify optimal conditions for potential efficacy. These studies will use relevant human fetal intestinal epithelial cells and animal models of newborn intestinal injury to test our working hypothesis. Our Phase 1 aims are: AIM 1: Define concentration-effect relationships and signaling activities of Nicotinamide using a preclinical model of human neonatal enterocyte injury and restitution and AIM 2: Evaluate the safety of and dosing regimen for nicotinamide in our established rat model of NEC and demonstrate proof of principle for attenuation of intestinal injury in our established newborn rat model of NEC by Nicotinamide. The specific goal of this phase 1 project is to demonstrate the proof of principle for the use of nicotinamide for NEC prevention and/or treatment. PUBLIC HEALTH RELEVANCE: Despite improvements in worldwide health and advances in medical practice the incidence of preterm birth continues to rise in virtually every region of the globe and is accounts for nearly 15% of all live births in the United States. Associated with this increased population of very low birth-weight infants are several medical conditions that are both life threatening and costly. One of these conditions is necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. We have preliminary evidence to demonstrate that nicotinamide is a potential therapeutic agent for NEC. We will carry out preclinical studies to define mechanistic actions and identify optimal conditions for potential efficacy using relevant human fetal intestinal epithelial cells and animal models of newborn intestinal injury.